Alzheimer's disease (AD) is a kind of degenerative neurological disease that progressively impairs cognitive and behavioral functions, posing a significant risk to the health of elderly population [1], [2]. One of the pathogenic factors of AD is the accumulation and deposition of β-amyloid protein (Aβ) in the brain tissue of patients, resulting in the generation of toxic Aβ oligomers and fibrils and triggering intracellular oxidative stress in neuroglial cells, which gradually causes neuronal synaptic dysfunction and ultimately culminates in neuronal death [3], [4]. In addition, the excess reactive oxygen species (ROS) in the AD brain originate from mitochondrial damage in neurons, activation and overexpression of related oxidative enzymes or the Fenton reaction between transition metal ions and Aβ, which can lead to oxidation and cellular damage and further exacerbate the progression of AD [5], [6]. Furthermore, Aβ promotes the elevation of ROS and triggers the onset of oxidative stress as evidenced by various research [6], [7]. Therefore, it is of paramount importance for the diagnosis and treatment of AD by developing multifunctional integrated drugs that can simultaneously inhibit Aβ aggregation, depolymerization of Aβ fibrils, image Aβ plaques and scavenge ROS.

Carbon dots (CDs), as one of the highly regarded carbon-based nanomaterials, have emerged as a novel Aβ inhibitor because of their exceptional characteristics, such as excellent fluorescence properties, abundant surface functional groups, good biocompatibility, low cytotoxicity, and facile synthesis [8], [9]. Compared to fluorescent CDs in the blue or green range, red fluorescent CDs have attracted considerable attention for their ability to deep penetration, reduce biological autofluorescence interference and minimize photodamage to healthy tissue, making them particularly suitable for in vivo applications [9], [10], [11], [12]. Some CDs have been demonstrated to facilitate the identification of Aβ monomers, oligomers and fibrils via energy transfer or luminescence resonance energy transfer [13], [14]. Furthermore, owing to their size effect and ample surface functional groups, some CDs can efficiently restrict Aβ aggregation by interacting with Aβ through electrostatic, hydrogen bonding, π-π stacking, and hydrophobic interactions [15], [16]. Moreover, some CDs can scavenge ROS due to their hydrogen-donating behaviors and electron transfer to the sp2 carbon core [17], [18]. Thus, rationally designed CDs are expected to be integrated drugs with theranostic potential for fighting against Aβ fibrillogenesis. There is evidence that it is possible to design fluorescent CDs with various functions because a synthetic CD can inherit the properties of its precursors [19], [20], [21]. In recent years, some CDs with desired properties against Aβ were synthesized by the selection of raw materials to partially preserve the features of the raw materials [22], [23], for instance, epigallocatechin gallate (EGCG) for its inhibitory effect [24], Congo red for its fluorescent response [25], and selenium for its scavenging of ROS on Aβ aggregation [26], [27]. However, it is still challenging to develop CDs of multifunctionality with theranostic potentials targeting Aβ fibrillogenesis.

Quercetin (Que) is a flavonoid, known for its diverse biological and pharmacological properties, including anticancer, antioxidant, cardioprotective, anti-inflammatory and neuroprotective effects[28], [29]. Nevertheless, the unique features of Que pose a challenge for its utilization because of its particular structure and intermolecular interactions, which make it inadequate bioavailability and low water solubility and stability[30]. To broaden the applicability of Que, researchers had employed various measures to boost its efficiency. Han and colleagues had effectively transformed Que molecule with low aqueous solubility into Que nanoparticles (NPs) with high water solubility via pulsed laser ablation[31]. Que NPs were employed to control the assembly of Aβ42 and displayed various functions of hindering the aggregation of Aβ42, destabilizing Aβ42 fibrils and reducing the oxidative stress caused by Aβ42. Subsequently, Qi et al. combined the antioxidant activity of selenium and the inhibitory effect of Que by utilizing Que, Na2SeO3, acacia and polysorbate 80 (P80) to develop Que-loaded selenium nanoparticles coated with acacia and P80, which was found to be effective in inhibiting the aggregation of Aβ42 as well as in exerting antioxidant activity[32]. The following new polymeric Que nanorods and Que-coated gold nanoparticles finally could inhibit hen egg white lysozyme aggregation by up to 50 % at 32 μg/mL and 30 μg/mL, respectively[33]. However, despite numerous attempts to improve the efficacy of the Que molecule for Aβ, the majority of synthesized Que-derived nanomaterials were monofunctional and displayed meagre inhibitory effects on Aβ aggregation and disaggregation capacity at low concentrations.

Hence, motivated by the capability of Que in inhibition of Aβ fibrillization and antioxidant property, we have herein proposed using Que as a carbon source to create a series of Que-derived CDs to boost its performance in the functioning against Aβ and to eliminate its disability of low water solubility. Moreover, to further endow Que-derived CDs with red-fluorescence emission, another heteroatom dopant that can modulate the fluorescence properties of CDs, p-phenylenediamine (p-PD), was selected as a nitrogen source, leading to the success in creating a red-fluorescence emission CDs. The red fluorescent CDs derived from Que and p-PD thus simultaneously achieved the multiple functionalities, including inhibition of Aβ aggregation, depolymerization of Aβ fibrils, fluorescent imaging of Aβ plaques, and scavenging of ROS at low concentrations (Scheme 1a).